The present invention relates to the stereochemistry of clopidogrel.
Atherosclerosis is the buildup of plaque in the wall of the arteries leading to a thickening and a reduction in elasticity of the arteries. Atherosclerosis results from injury to the inside layer of the artery. The injury is caused by common activities and diseases such as high cholesterol, high blood pressure, smoking and infection.
Plaques form on the inner walls of the artery at these sites of injury. The plaques are mainly composed of fatty tissue and smooth muscle cells. The formation of plaque often leads to blood clotting due to platelet aggregation at the site of the injury. This clotting may result in a reduction or elimination of blood flow to vital organs, causing heart attacks or other serious conditions. The plaque may also rupture and send a blood clot through the artery, referred to as an embolus, which if deposited in a smaller blood vessel may completely block blood flow.
Antiplatelet activity is desirable in fighting the often fatal results of atherosclerosis. Clopidogrel is an inhibitor of induced platelet aggregation which acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration.
The chemical name of clopidogrel is methyl (+)-(S)-xe2x88x9d-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate. It has the following structure: 
Clopidogrel is disclosed in U.S. Pat. No. 4,529,596 (EP 99802, JP 59027895), U.S. Pat. Nos. 6,258,961, 5,036,156 (EP 420706, JP 3120286), U.S. Pat. No. 6,080,875 (EP 971915, JP 2001513806), U.S. Pat. No. 6,180,793 (EP 981529, JP 2001525829), FR 2769313, all of which are incorporated herein by reference for their disclosure and preparation of clopidogrel. U.S. Pat. No. 4,529,596 discloses a racemic mixture of clopidogrel and processes for preparing such mixture. U.S. Pat. No. 5,036,156 discloses a method for preparing an intermediate in the synthesis of clopidogrel, 2-chloro-xcex1-bromophenylacetic acid, and a process for condensing its methyl ester with tetrahydrothienopyridine. FR 2769313 discloses an intermediate in the synthesis of clopidogrel, (R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic acid methyl ester, and processes for its preparation. FR 2769313 further discloses converting the ester to clopidogrel by nucleophilic substitution with tetrahydrothienopyridine. U.S. Pat. No. 5,036,156 discloses preparation of pyridine drivatives by reacting a benzaldehyde with tribromomethane and potassium hydroxide in water and in the presence of an inert solvent.
Clopidogrel""s platelet inhibiting activity makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. U.S. Pat. No. 5,576,328 describes a method of preventing the occurrence of a secondary ischemic event by administration of clopidogrel, and is incorporated herein by reference.
Recent studies have shown that clopidogrel is more effective in blocking platelet aggregation than aspirin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than aspirin even at much lower dosage. A dosage of 75 mg of base equivalent has been shown to be more effective than a dosage of 325 mg of aspirin. In addition to being more effective, clopidogrel produces much less gastrointestinal bleeding than aspirin.
Clopidogrel is administered as its bisulfate (syn. hydrogensulfate) salt. Clopidogrel bisulfate has an empirical formula of C16H16Cl NO2S.H2SO4. It is currently being marketed as PLAVIX(copyright) tablets, which contain about 98 mg clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base. PLAVIX(copyright) is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. It dissolves freely in methanol, somewhat in methylene chloride, and poorly in ethyl ether.
The enantiomer (S) clopidogrel is particularly preferred since it is the pharmaceutically active compound.
U.S. Pat. No. 6,080,875 (EP 971915, JP 2001513806), incorporated herein by reference, prepares (S) clopidogrel by reaction of sodium 2-thienylglycidate with (S) 2-chloro phenyl glycine in the presence of cyanoborohydride.
U.S. Pat. No. 6,180,793 (EP 981,529, JP 2001525819) and related publications WO 98/51681, WO 98/51682 and WO/51689, incorporated herein by reference, prepare the (S) enantiomer by methods that control the chirality of the intermediates used in the synthesis of clopiodogrel to reduce formation of the (R) enantiomer. U.S. Pat. No. 6,180,793 and the related art disclose processes for synthesizing (S) clopidogrel by reaction of an activated form of 2-thiophene ethanol with (S)-2-chlorophenyl glycineamide, (S)-2-chlorophenyl-xcex1-amino acetonitrile or (S)2-chlorophenyl glycine methyl ester. After condensation, the resulting compound is cyclicized, hydrolyzed and esterified.
WO 98/39286, incorporated herein by reference, discloses a racemization process for phenyl glycine esters. A mixture of enantiomers of phenyl glycine ester is treated with a carbonyl compound in the presence of a carboxylic acid and a single enantiomer of an N-protected xcex1-amino acid as resolving agent. The formation of an imino intermediate causes the racemization of the starting product and the precipitation of a single diastereomeric salt. After hydrolysis of the salt, an enantiomer of phenyl glycine ester is obtained.
U.S. Pat. No. 4,847,265 (EP 291459, JP 63203684) discloses methods for separating one enantiomer of clopidogrel from another by selective crystallization of the camphor sulfonate of the (S) enantiomer. The ""265 patent discloses crystallizing the (S) enantiomer from dimethylformamide (xe2x80x9cDMFxe2x80x9d), ketones, and alcohols, though crystallization with acetone is primarily disclosed. U.S. Pat. No. 5,132,435 (EP 465358, JP 3055819), U.S. Pat. No. 6,215,005 and U.S. Pat. No. 6,258,961, incorporated herein by reference, also disclose separating the (S) enantiomer of clopidogrel by crystallization of the camphor sulfonate from acetone.
U.S. Pat. No. 5,204,469 (EP 466569, JP 4230387) discloses an enantioselective process for synthesis of clopidogrel through reaction of (+)-2-chloro phenylglycine and an activated form of 2-thiophene ethanol followed by cyclization with formaldehyde.
WO 00/27840 (EP 1129087) discloses using a base to racemize an amide intermediate used in the synthesis of clopidogrel. The process of WO 00/27840 requires going through an amide intermediate, which is not always used in preparing clopidogrel, as illustrated by Examples 1 and 2 of the present invention. It is advantageous to prepare clopidogrel, and then racemize clopidogrel rather than the intermediate, and to skip the necessary conversion of the amide intermediate to an ester as required in WO 00/27840. WO 02/059128 also generally discloses racemization of an intermediate of clopidogrel and clopidogrel with an equimolar amount of a base, though an actual example is not provided regarding racemization of clopidogrel.
A problem with the preparation of clopidogrel is the presence of a therapeutically inactive enantiomer, the (R) enantiomer. The presence of the (R) enantiomer results in contamination of the main product, and reduces the yield by being a waste product. There is a need in the art to prepare the (S) enantiomer of clopidogrel substantially free of the (R) enantiomer in a facile manner suitable on an industrial scale.
In one aspect, the present invention provides a process for preparing (S) clopidogrel free base or a pharmaceutically acceptable salt thereof comprising the steps of reacting a mixture of (R) and (S) clopidogrel free base with levorotatory camphor sulfonic acid in a mixture of a C5 to a C12 hydrocarbon and a suitable co-solvent to precipitate (S) clopidogrel camphor sulfonate and converting (S) clopidogrel camphor sulfonate to clopidogrel free base or a pharmaceutically acceptable salt thereof. A preferred salt is the bisulfate salt. Preferably, the mixture contains from about 3% to about 20% (vouvol) of the co-solvent, more preferably about 5% to about 10% of the co-solvent. Preferably, the co-solvent is selected from the group consisting of DMF, butanol and acetone. Preferably, the hydrocarbon is an aromatic hydrocarbon, more preferably xylene, benzene, toluene and chlorobenzene, and most preferably toluene.
In another aspect, the present invention provides a process for racemizing (R) clopidogrel comprising reacting (R) clopidogrel with a catalytic amount of a base in a solvent to convert a portion of the (R) clopidogrel to (S) clopidogrel. Preferred bases are sodium t-butoxide, potassium t-butoxide, diisopropylamide, sodium hydride, potassium hydride, sodium methoxide and potassium methoxide. Preferably, the solvent is a hydrocarbon as described above. Preferably, the racemizing is carried out at a temperature of less than about 20xc2x0 C., more preferably at a temperature of about 0xc2x0 C.
In another aspect, the present invention provides a process for preparing a pharmaceutically acceptable salt of (S) clopidogrel comprising the steps of reacting a first mixture of (R) and (S) clopidogrel with levorotatory camphor sulfonic acid in a mixture of a C5 to a C12 hydrocarbon and a suitable co-solvent to precipitate a first (S) clopidogrel camphor sulfonate, racemizing (R) clopidogrel remaining in the mixture of the hydrocarbon and the co-solvent by reaction with a catalytic amount of a base to obtain a second mixture of (R) and (S) clopidogrel, precipitating both forms of clopidogrel from the second mixture of (R) and (S) clopidogrel by adding an acid to form a salt, converting the salt to a free base, repeating the first step of the process to obtain a second (S) clopidogrel camphor sulfonate from the free base and converting the first and second (S) clopidogrel camphor sulfonate to a pharmaceutically acceptable salt of (S) clopidogrel.
In another aspect, the present invention provides a process for preparing a pharmaceutically acceptable salt of (S) clopidogrel comprising the steps of reacting a first mixture of (R) and (S) clopidogrel with levorotatory camphor sulfonic acid in a mixture of a C5 to a C12 hydrocarbon and a suitable co-solvent to precipitate a first (S) clopidogrel camphor sulfonate, racemizing the (R) clopidogrel remaining in the mixture of the hydrocarbon and the co-solvent by reaction with a catalytic amount of a base to obtain a second mixture of (R) and (S) clopidogrel, reacting the second mixture of (R) and (S) clopidogrel with levorotatory camphor sulfonic acid to precipitate a second (S) clopidogrel camphor sulfonate and converting the first and the second (S) clopidogrel camphor sulfonate to a pharmaceutically acceptable salt of (S) clopidogrel.
In another aspect, the present invention provides a process for preparing (S) enantiomer of clopidogrel bisulfate comprising the steps of reacting a solution of (R) and (S) clopidogrel in toluene with a solution of levorotatory camphor sulfonic acid in DMF, thereby forming a first clopidogrel (S) camphor sulfonate as a precipitate, removing the DMF and excess camphor sulfonic acid, racemizing the (R) clopidogrel by reaction with a catalytic amount of a base in the toluene to form a mixture of clopidogrel (R) and (S), reacting the mixture of (R) and (S) clopidogrel with levorotatory camphor sulfonic acid in the toluene, thereby forming a second (S) clopidogrel camphor sulfonate as a precipitate and converting the first and the second (S) clopidogrel camphor sulfonate to (S) clopidogrel bisulfate.
In another aspect, the present invention provides a process for preparing (S) clopidogrel bisulfate comprising the steps of reacting a solution of clopidogrel (R) and (S) in toluene with a solution of levorotatory camphor sulfonic acid in DMF, thereby forming a first clopidogrel (S) camphor sulfonate as a precipitate, removing the DMF and excess camphor sulfonic acid, racemizing the (R) clopidogrel remaining in the toluene by reaction with a catalytic amount of a base in the toluene to form a mixture of (R) and (S) clopidogrel, adding sulfuric acid to the mixture of (R) and (S) clopidogrel to precipitate clopidogrel (R) and (S) as a bisulfate, converting the bisulfate to a free base, repeating the first step of the process to obtain a second (S) clopidogrel camphor sulfonate from the free base and converting the first and the second (S) clopidogrel camphor sulfonate to (S) clopidogrel bisulfate.
In another aspect, the present invention provides a process for preparing (S) clopidogrel bisulfate comprising the steps of reacting a solution of (R) and (S) clopidogrel in toluene with a solution of levorotatory camphor sulfonic in DMF, thereby forming (S) clopidogrel camphor sulfonate as a precipitate and converting (S) clopidogrel camphor sulfonate to clopidogrel bisulfate.
In another aspect the present invention provides a process for preparing (S) clopidogrel free base or a pharmaceutically acceptable salt thereof comprising the steps of reacting a mixture of (R) and (S) clopidogrel free base with levorotatory camphor sulfonic acid in a C5 to a C12 hydrocarbon to precipitate (S) clopidogrel camphor sulfonate and converting (S) clopidogrel camphor sulfonate to clopidogrel free base or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for preparing a pharmaceutically acceptable salt of (S) clopidogrel comprising the steps of reacting a mixture of (R) and (S) clopidogrel with levorotatory camphor sulfonic acid in a C5 to a C12 aromatic hydrocarbon to precipitate (S) clopidogrel camphor sulfonate, racemizing the (R) clopidogrel remaining in the hydrocarbon by reaction with a catalytic amount of a base in the hydrocarbon to obtain a mixture of (R) and (S) clopidogrel, recovering the (S) clopidogrel and converting the (S) clopidogrel to a pharmaceutically acceptable salt.